- Email: [email protected]
Time to pregnancy and preterm delivery
Time to Pregnancy
and Preterm
Delivery
TINE BRlNK HENRIKSEN, MD, PhD, DONNA DAY BAIRD, PhD, J0RN OLSEN, MD, PhD, MORTEN HEDEGAARD, MD, PhD, NIELS J0RGEN SECHER, MD, AND ALLEN J. WILCOX, MD, PhD Objective:
To
higher
of preterm delivery. We used data from
risk
Methods: studies mately
test
whether
subfertile two
women
may
population-based
be
at
cohort
on risk factors and pregnancy outcome for approxi20,000 deliveries in three major Danish obstetric
departments. nant women departments
The Aalborg-Odense study comprised all pregattending routine antenatal care at two obstetric from 1984 to 1987. In all, 11,850 women (86%)
filled in a questionnaire Aarhus study addressed weeks’ gestation from was returned by 6857 with speak
chronic Danish.
at about 36 weeks’ gestation. The women at the routine visit near 16 1989 (80%).
to 1991; a study questionnaire Both studies excluded women
illnesses, multiple Only women with
fetuses, planned
and inability to pregnancies were
included in the analysis. In all, 8855 and Aalborg-Odense and Aarhus, respectively,
3985 women from were eligible for
the analyses. In according to their
both cohorts, waiting time
women were categorized to pregnancy (O-6 months,
7-12 months, and greater than 1 year) and according to examination or treatment for infertility (yes, no). Preterm delivery was defined as birth before 37 completed weeks.
Results: Compared with women who less before they conceived, women
tried for 6 months or who tried for 7-12
months had the adjusted
1.3 times (95% risk of preterm
interval in both
women with had adjusted
a time to pregnancy relative
risks
confidence delivery for
CI 1.1, 2.21 for Aalborg-Odense Aarhus. The results remained
[CI] 0.8, 2.1) cohorts, and
of greater than 12 months
preterm and similar
delivery
of 1.6 (95%
1.7 (95% CI 1.1, 2.6) for after excluding women
with infertility treatment. Conclusions: Pregnant women with subfertility and clinically defined infertility are more prone to preterm delivery, even in the absence of infertility 1997;89:594-9. 0 1997 by The
tricians
treatment. American
(Obstet College
Gynecol of Obste-
and Gynecologists.)
From the Perinntal Epidemiological Rrseurch Unit, Department @ Obstetrics and Gyrzecology, Aarhus Uniaersity Hospital, Denmark; the Danish Epidemiology Science Center, Institute cf Epidemiology and Social Medicine, Aarhus University, Denmark; and the Epidemiology Branch, National Institute qf Enz~ironmental Health Sciences, Research Triangle Park, North Carolina.
594
0029-7844/97/$17.00 PI1 SOO29-7844(97)00045-B
Assisted reproduction has been used for decades.’ Surgical procedures or hormonal treatment with or without intrauterine insemination, gamete intrafallopian transfer (GIFT), or in vitro fertilization (IVF) are used widely in couples who have difficulty getting pregnant.‘,* Women enrolled in IVF or GIFT programs have high rates (10 -20%) of preterm delivery, even with singleton pregnancies. 1*3-8 It is not clear whether these high rates of preterm delivery are due to the treatment or to some underlying problems related to infertility. An increased risk of preterm delivery has been attributed to elevated levels of relaxin after the administration of gonadotropins” and to possible intrauterine trauma or infections from the use of catheters during the procedures.” Some studies,“-I” but not a11,i4,‘” have suggested that infertility itself may be an independent risk factor for preterm birth. If women treated for infertility have a higher a priori risk of adverse pregnancy outcome, then those adverse effects may mistakenly be attributed to the treatment. We tested the hypothesis that subfertile women may be at higher risk of preterm delivery regardless of fertility treatment. Data from two Danish populationbased studies were used to evaluate the association between subfertility (measured as time to pregnancy) and preterm delivery.
Materials and Methods Two large Danish population-based studies16,17 collected data on risk factors and pregnancy outcome. Both of these projects were approved by the Regional Committees for Ethics in Science. Both studies obtained information about potential risk factors for adverse pregnancy outcome using questionnaires administered during pregnancy. Briefly, the first was part of a study that included all pregnant women in two major Danish cities (Aalborg and Odense) during a 3-year period (1984-1987). Midwives handed out the questionnaires
Obstetrics & Gynecology
at the routine antenatal visit in the 36th gestational week. More than 95% of all women with singleton pregnancies in the two regions (n = 13,815) received the questionnaire, and 11,850 (86%) responded. Some women did not attend the antenatal care program. Accordingly, they did not receive the questionnaire. Some women delivered before the antenatal visit, and in a few instances the midwife may simply have forgotten to hand out the questionnaire. Women with cardiovascular disease, epilepsy, rheumatic arthritis, diabetes, or cancer were excluded (n = 188). Of the remaining women, 303 provided no information on gestational age or time to pregnancy, leaving 11,306 women eligible for analyses. Of these, 8855 (78.3%) had planned their pregnancy. Data included maternal characteristics (age, height, pre-pregnancy weight), job history, smoking, and drinking and eating habits. Women were asked if they had ever been examined or treated for infertility, and the time between discontinuing the use of contraception and pregnancy (“pregnant in spite of contraceptive use,” O-6 months, 7-12 months, and more than 1 year). Obstetric and medical history and information about the outcome of pregnancy were collected from birth certificates and the women’s medical records. The second study was of all pregnant women attending routine antenatal care in the city of Aarhus during a 2-year period (1989-1991). The study excluded women who were unable to speak Danish, were pregnant with more than a single fetus, or were suffering a fetal death before 28 completed weeks’ gestation (n = 964). Some women delivered twice during the period; only the first pregnancy was included. In all, 8536 women were eligible for the study. At the routine antenatal visit at about 16 weeks’ gestation, women were asked to complete two questionnaires: a basic questionnaire and a primary study questionnaire. The first requested the women’s medical history, determined eligibility, ascertained the date of the last menstrual period and cycle length, and collected data on smoking and alcohol consumption. This questionnaire also obtained information on whether the pregnancy was planned and the waiting time to pregnancy in years and months. Data obtained by the second, more extensive study questionnaire included psychosocial factors, marital status, education, and occupational status. Immediately after delivery, the attending midwife made a structured report on the obstetric and medical complications during pregnancy, the course of delivery, and the condition of the newborn. These data were cross-validated by a research midwife using hospital records. The basic questionnaire was returned by 8377 (98%) of the women in the cohort, and the study questionnaire by 6857 (80%). Gestational age at delivery was calculated
VOL.
89, NO.
4, APRIL
1997
Table
1. Time to Pregnancyby Preterm Delivery: The
Aarhus Cohort Study Time to pregnancy
(mo)
AIl women (n = 3985) 56 7-12 >12 Women without infertility treatment (n = 3757) ~6 7-12 >12
n
Preterm delivery
Relative risk
2978 486 521
99 (3.3%) 21 (4.3%) 31 (6.0%)
Reference 1.3 1.8
2948 431 339
96 (3.3%) 19 (4.2%) 20 (5.9%)
Reference 1.3 1.8
from ultrasonographically determined fetal biparietal diameter, obtained before 21 completed weeks’ gestation in more than 80% of the women.” All women were offered a routine ultrasound scan; however, not all women accepted. In women without an early scan, gestational age was estimated from the last menstrual period, adjusted for the woman’s usual cycle length to a length of 28 days. Women with cardiovascular, pulmonary, or kidney diseases;diabetes or other metabolic diseases;or epilepsy diagnosed before pregnancy were excluded (n = 233). Gestational age was missing in 74 cases,leaving a study cohort of 6550women. Of these, 3985(60.8%) had planned their pregnancy. Preterm delivery was defined as delivery before 37 completed weeks. Analyses were restricted to women whose pregnancies were planned. Multiple variables were taken into account using multiple logistic regression.” Odds ratios (ORs) are presented with 95% confidence intervals (Us); statistical significance was defined as a two-sided P < .05. Potential confounding variables (categorized as shown in the tables) were tested in the multivariate analyses as dummy variables; if the variables changed the estimate of the association between time to pregnancy and preterm delivery by 10% or more, they remained in the final model.”
Results The overall rate of preterm delivery in the Aarhus study was 3.8%. This rate was the same for both planned and unplanned pregnancies. Because of the late timing of the questionnaire in the Aalborg-Odense study, the overall rate of preterm delivery was smaller (2.7%). The preterm delivery rate among planned pregnancies (2.6%) was close to that among unplanned pregnancies (3.0%). Tables 1 and 2 show the distributions of preterm deliveries by time to pregnancy. In both cohorts, the
Henriksen
et al
Fertility
and Preterm
Delivery
595
Table
2.
Time
Time to Pregnancy by Preterm Delivery: The Aalborg-Odense Cohort Study to pregnancy
(mo)
All women (n = 8855) 56 7-12 >12 Women without examination or treatment for infertility (n = 8179) ~6 7-12 >12
n
Preterm delivery
Relative risk
6529 152 (2.3%) 857 26 (3.0%) 1469 54 (3.7%)
Reference 1.3 1.6
6372 151 (2.4%) 825 23 (2.8%) 982 41 (4.2%)
Reference 1.2 1.8
rate of preterm deliveries increased with increasing time to pregnancy. Compared with women who succeeded in getting pregnant within 6 months, women with a time to pregnancy of more than 12 months had 1.6 and 1.8 times the risk of preterm delivery in the Aarhus and Aalborg-Odense studies, respectively. This pattern did not change after excluding women who had examination or treatment for infertility (Tables 1 and 2). Table 3 shows the distribution of preterm delivery by time to pregnancy, dichotomized at 1 year and stratified by potential confounding factors, for both studies. The bivariate associations shown in Tables 1 and 2 were consistent across strata: With few exceptions, the percentage of women with preterm deliveries was higher among women who took longer than 1 year to conceive. The pattern was very similar when time to pregnancy was dichotomized at 6 months (data not shown). Table 4 shows the adjusted association between time to pregnancy and preterm delivery in the two cohorts. Few of the potential confounders listed in Table 3 affected the association. Compared with women who tried for 6 months or less before they conceived, women who tried for 7-12 months had 1.3 times the risk of preterm delivery. This excess risk was not statistically significant, although it was consistent across both cohorts (Table 4). In both studies, women with a time to pregnancy of more than a year had a significantly higher risk of preterm delivery compared with women who conceived within 6 months. The adjusted ORs for preterm delivery in the two studies were 1.6 (95% CI 1.1, 2.2) and 1.7 (95% CI 1.1, 2.6), respectively. The results were not changed by excluding women with early-pregnancy bleeding, previous preterm delivery, previous spontaneous or induced abortions, examination or treatment for infertility, or induced deliveries.
Discussion Time to pregnancy of more than a year is used by clinicians to identify couples who might benefit from
596
Henriksen
et al
Ferti/ity and Preterm Delivery
infertility treatment. Among those who became pregnant in less than 1 year, our data allowed us to subcategorize fertility further into two groups: the more fertile who conceived in O-6 months and the less fertile who became pregnant in 7-12 months. Women with a longer time to pregnancy had an increased risk of preterm delivery in both cohorts. Women with a time to pregnancy of 7-12 months had a 30% higher risk, and women with a time to pregnancy of more than 1 year had a 60% higher risk than women who conceived within half a year of trying. Joffe and Lii3 found that pregnancies ending in a preterm delivery took 15% longer to conceive than other live births. However, the risk of preterm delivery among untreated clinically infertile women, ie, women with a time to pregnancy of more than a year, could not be derived from their study. Furthermore, the study was based on asking 33-year-old women about the outcome of past pregnancies. Even though recall of time to pregnancy and preterm delivery may be fairly accurate,‘l recall bias may be introduced by the women’s knowledge of the pregnancy outcome. We avoided this potential bias by collecting information on time to pregnancy before delivery. Most other studies on subfertility and pregnancy complications were small, with insufficient statistical power to explore the relation with preterm delivery.2~22~23 Furthermore, it has been impossible to rule out the effect of treatment because women with and without infertility treatment were not separated.‘2,‘5,22,23 Our participation rates were between 80% and 90%. Preterm delivery was slightly more common among non-responders. Thus, selection bias could occur if women with a shorter time to pregnancy were less likely to participate. However, in the Aarhus study, we found the same association between time to pregnancy and preterm delivery among women who declined to fill in the larger study questionnaire as among responders. Information on time to pregnancy among nonresponders was not available in the Aalborg-Odense study, but this study had a higher overall response rate, and selection bias due to non-response seems even less likely. It is possible that selection bias could occur by restricting the study population to women with planned pregnancies: 24 If the more fecund women who conceived despite contraceptive use had more preterm deliveries but are excluded, it will lead to an overestimation of the true association between time to pregnancy and preterm delivery. We found the same rate of preterm deliveries among planners and non-planners in the Aarhus study. Furthermore, in the Aalborg-Odense data, we had information about non-planners who became pregnant despite contraceptive use (n = 584).
Obstetrics 0 Gynecology
Table
of Preterm Delivery and Time to Pregnancy Dichotomized at 12 Months by Maternal Characteristics, Obstetric History, Life-Style, and Social Factors: The Aarhus Cohort Study (12 = 3985) and the Aalborg-Odense Cohort Study (n = SSS5)
3. Rate
_ Variable Age (y) <25 25-29 30-34 235 Pre-pregnancy ~60 60-69 270 Height (cm) Cl65 165-169 ,170 Parity 0
weight
M
VOL.
89, NO.
The Aarhus cohort -~-. ..I_TTP > 12 mo (preterm %)
The Aalborg-Odense TTP 5 12 mo (preterm 7~)
n
TTP > 12 mo (preterm 9:)
cohort
-___
TTI’ 5 12 mo (preterm 70)
534 1762 1199 490
7.8 6.0 4.3 7.9
3.7 3.9 2.8 3.3
2385 3965 1936 563
4.6 3.7 3.9 1.3
2.3 2.6 1.8 3.5
1872 1426 622
5.4 4.7 9.0
3.5 3.1 4.1
4500 2855 1183
4.6 2.3 2.3
2.6 2.2 2.3
1152 1258 1524
6.1 8.4 3.6
3.8 3.4 3.2
3156 2620 2582
4.0 2.1 3.9
2.6 2.0 2.5
2060 1442 479
5.8 6.3 6.4
4.2 2.0 4.9
4164 3633 1058
4.0 3.0 4.5
2.7 1.9 2.9
2060 1771 150
5.8 5.7 14.3
4.2 2.1 9.6
1389 1792 804
5.0 5.6 8.8
3.3 3.3 4.1
3141 4271 1443
3.9 2.8 5.7
2.7 2.2 2.5
1389 1577 1019
5.0 5.4 9.0
3.3 3.0 4.4
2229 1739
5.6 6.6
2.9 4.2
5200 3655
3.7 3.7
2.6 2.3
316 1185 2333
9.3 5.9 5.3
5.0 4.1 3.1
1300 4473 3063
3.1 3.3 4.9
2.1 2.6 2.2
2729 603 612
4.7 9.5 7.8
3.4 4.4 3.2
7202 1363 281
3.3 5.7 5.0
2.4 2.6 1.5
2711 1195
6.5 5.4
2.8 5.1
4731
3.3
2.4
1282 2803
4.9 3.8
2.4 2.5
4090 3287 1316
3.8 3.5 3.9
2.5 2.1 3.5
3025 5036 794
2.4 4.0 3.7
3.5 2.2 3.7
(kg)
22 Previous preterm delivery Primiparous 0 21 Previous spontaneous abortion Primigravida 0 21 Previous induced abortion I’rimigravida 0 21 Marital status Married Cohabitating or living alone Education (y) 7-9 10-11 212 Work status Employed Unemployed Studying Smoking Non-smoker Smoker 1-9 cigarettes/d ~10 cigarettes/d Caffeine intake (mg/d)
---
992 1373 1619
8.1 5.3 5.2
3.1 3.3 3.9
2025 1728 180
6.6 5.4 7.1
3.7 3.0 5.3
3183 802
5.4 7.5
3.1 4.8
3297 638
5.2 9.1
3.2 4.7
to pregnancy.
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Table
4.
Time to Pregnancy and Preterm Delivery: Odds Ratios and 95% Cbnfidence Intervals Adjusted for Parity and Smoking Habits by Logistic Regression Analysis, the Aarhus and the Aalborg-Odense Cohort Studies
Time to pregnancy (mo) All women 56 7-12 >12 No infertility treatment* 56 7-12 >12
The Aarhus
The AalborgOdense cohort?
cohort*
OR
957G CI
OR
95% CI
1 1.3 1.7
(n = 39851 Reference 0.8,2.1 1.1,2.6 (n = 3757)
1 1.3 1.6
(n = 8855) Reference 0.8,2.0 1.1,2.2 (n = 8179)
1 1.3 1.6
Reference 0.8,2.1 1.0,2.7
1 1.2 1.8
Reference 0.7, 1.8 1.2,2.2
OR = odds ratio; CI = confidence interval. * Adjusted for smoking and parity. + Adjusted for parity. * For the Aarhus cohort, no infertility treatment; for the AalborgOdense cohort, no examination or treatment for infertility.
These women had a decreased rate of preterm deliveries (2.2%), consistent with the general association between higher fertility and lower rates of preterm birth. Although known risk factors for preterm delivery are few,” we tested several variables as potential confounders. Only parity and smoking had a strong enough effect to be included in our final models. Furthermore, our association was not mediated by earlypregnancy bleeding, infertility treatment, or more induced deliveries among the women with a longer time to pregnancy. In the Aarhus data, there was a stronger association between time to pregnancy and preterm delivery am.ongparous women than among nulliparous women (Table 3). However, this was not corroborated by the Aalborg-Odense data. When subfertility is defined by time and not by the menstrual cycle, a long time to pregnancy may be due to long cycles. If estimation of gestational age is based on the date of the last menstrual period and cycle length is not taken into account, gestational age is overestimated and the number of preterm deliveries is underestimated in women with long cycles. This bias (which may mask a potential association between time to pregnancy and preterm delivery) has not been addressed in previous studies. However, in the Aarhus study, most gestational-age estimates were based on early ultrasound scanning, eliminating this problem. Most previous studies of pregnancy outcome among women treated for infertility compared the outcome among treated women with that of the general population. 1,6-8,‘5,25 The higher rate of twin and triplet pregnancies among women treated for infertility contributes
598
Henriksen
et al
Fertility and Preterm Delivery
some of the difference
in the rates of txeterm I
deliveries.
Thus, comparisons are often restricted to singleton births. However, the possibility has rarely been addressed that the treated population may be otherwise noncomparable with the background population. To our knowledge, no study has matched the comparison group with the treatment groups for the length of time to pregnancy, or otherwise controlled for this variable. Previous studies on singleton pregnancies primarily obtained by IVF methods revealed relative risks of 1.6-2.5 and absolute risk increases of 3.8-7.8% compared with untreated populations.‘,3,4-7 Most of these studies adjusted for differences in age and parity between treated and untreated women. However, our data suggest that the infertility history of treated women could explain much of the difference in the preterm delivery rate between women with and without infertility treatment. The association we observed between subfertility (or clinically defined infertility) and preterm delivery suggests shared causes.For instance, chlamydia infection of the female genital tract has been related to both infertility and preterm delivery.26-28 Evidence also exists that life-style factors, such as female smoking, may be related to subfertility29,30 as well as to the risk of preterm delivery,3l although smoking could not account for the association in our study. Another example is intrauterine exposure to diethylstilbestrol, which produces female infertility and preterm delivery.32,33In this case, the link may be the uterine anomalies associated with the exposure.34 Yet another mechanism could be introduced by the waiting time per se: Recent studies have shown that psychological stress’7*35 is associated with preterm delivery. Accordingly, an association between time to pregnancy and preterm delivery would appear if stressincreaseswith increasing time to pregnancy. In the Aarhus cohort, stress as measured by the General Health Questionnaire and Life Events17,35did not explain our findings (data not shown). To address the possible biologic mechanisms of our findings, further studies are needed on the association between preterm delivery and specific categories of infertility, such as infertility related to hormonal or mechanical disturbances. Furthermore, studies that identify subcategories of preterm delivery, such as preterm delivery preceded by labor or rupture of membranes, may provide valuable clues regarding a shared etiology of infertility and preterm birth.
References 1. MRC Working Party on Children Conceived tion. Births in Great Britain resulting from 1978-87. BMJ 1990;300:1229-33.
by In Vitro Fertilisaassisted conception,
Obstetrics & Gynecology
2. Hill GA, Bryan S, Herbert CM, Shah tions of pregnancy in infertile couples:
DM, Wentz AC. ComplicaRoutine treatment versus
assisted 3. Saunders
1990;75:790-4. PAL. The Australian
reproduction. DM, Mathews
Obstet Gynecol M, Lancaster
ter: Current research and future N Y Acad Sci 1988;541:7-21. 4. Doyle I’, Beral V, Maconochie weight resulting
role.
A preliminary
N.
l’reterm
and small-for-gestational-age from in-vitro fertilization.
23. Regis-
report.
Ann
low
birth-
delivery,
in livebom Hum Reprod
of infertility:
A prospective
1087-92. Bhalla AK,
Sarala
study.
G, Dhaliwal
Aust N Z J Obstet Gynaecol 24. Baird DD, Weinberg CR, associated with contraceptive
Br J Obstet
L. Pregnancy
1991;98:
following
infertility.
1992;3:249-51. Schwingl P, Wilcox AJ. Selection practice in time-to-pregnancy
ies. Ann N Y Acad Sci 1994;709:156-64. 25. Ezra Y, Schenker JG. Appraisal of in vitro Gynecol Reprod Biol 1993;48:127-33.
singleton babies 1992;7:425-8.
Gynaecol
fertilization.
bias stud-
Eur J Obstet
5. Olivennes F, Rufat P, Andre B, Pourade A, Quiros MC, Frydman R. The increased risk of complication observed in singleton pregnancies resulting from in-vitro fertilization (IVF) does not seem to be
26. Czerwenka K, Heuss F, Hosmann J, Manavi M, Jelincic D, Kubista E. Salpingitis caused by Chlamydia trachomatis and its sign& cance for infertility. Acta Obstet Gynecol Stand 1994;73:711-5.
related to the IVF method itself. Hum Reprod 1993;8:1297-300. 6. Tan SL, Doyle I’, Campbell S, Beral V, Rizk B, Brinsden P, et al. Obstetric outcome of in vitro fertilization pregnancies compared
27.
with
normally
conceived
pregnancies.
167:778-4. 7. van Diiring V, Maltau JM, Ertzeid G, et al. Pregnancies,
Forsdahl births
fertilization in Norway, 1988-91. 2054-60. 8. Wang JX, Clark AM, Kirby CA, G, et al. The obstetric
outcome
in-vitro fertilization/gamete 1994;9:141-6. 9. Bell RJ, Eddie LW, Relaxin in human gous radioimmunoassay. 10. Berkowitz miol Rev
12. Ghazi tility:
J Obstet
Tidsskr
Nor
Philipson
of preterm
study
preterm birth: A case 165:1290-6. 15. Varma TR, Pantel RH,
study.
Bhathenia
Am
RK.
Outcome
M, Henriksen
TB, Sabroe
and preterm NJ, Weis-Bentzon
Gynecol
1991;
of pregnancy
after
women
S. Applied logistic regression. New York: 1989. and variable selection in epidemiologic
22.
time-to-pregnancy. Li TC, MacLeod
Fertil Steril 1993;60:99-104. I, Singhal V, Duncan SLB.
The
neonatal
of pregnancy
a previous
VOL.
89, NO.
4, APRIL
1997
in women
M. Long-term
with
obstetric
recall
preterm
deliv-
W, Thaler H. The role of infection Obstet Gynecol 1988;71:723-6.
31
consumption and infertility. Int J Epidemiol 1983;12:179-84. Wisborg K, Henriksen TB, Hedegaard M, Secher NJ. Smoking
P, Schindt
AV,
oxide.
DL, Shy CM, Wilcox as dental assistants
30
32
of nitrous
in the
Damsbo
preterm delivery. Br J Obstet Gynaecol Herbst AL, Hubby MM, Blough RR, pregnancy experience in DES-exposed Herbst among
J Reprod
Med
N Engl
N. Tobacco
Frey
alcohol and
1996;103:800-5. Azizi F. A comparison and DES-unexposed
NJ, Hatch
life events affect duration of gestation Epidemiology 1996;7:339-45.
requests
use,
of
K. Abortion and pregnancy loss women. Semin Reprod Endocri-
Am J Obstet Gynecol 1986;154:1312-8. Hedegaard M, Henriksen TB, Secher
reprint
1992;327:
1980;24:62-9.
AL, Senekjian EK, diethylstilbestrol-exposed
stressful delivery?
J Med
M. Upper
MC, and
Sabroe risk
genital women. S. Do
of preterm
to:
Tine Brink Henriksen, MD, PhD Perinatal Epidemiological Research Unit Department of Obstetrics and Gynecology Aarhus University Hospital Skejby Aarhus N, DK-8200
Denmark
in a longituin predicting
21.
outcome
in
1993;307:234-9. growth of the
analysis. Am J Public Health 1989;79:340-9. Joffe M, Villard L, Li Z, Plowman R, Vessey
and
Pregnancy Mycoplasma
exposed to high 993-7. Olsen J, Rachootin
Address
smok-
NJ. Psychological
BMJ Normal
diameter and the abdominal diameter An evaluation of the two parameters Acta Obstet Gynecol Stand 1985;64:65-70.
19. Hosmer DW, Lemeshow John Wiley and Sons, 20. Greenland S. Modeling
of
Spontaneous
pregnant
retardation
DD, Weinberg CR, Shore among women employed levels
Adverse and
no1 1989;7:124-9. Kaufman RH, Adam E, Noller K, Irwin JF, Gray tract changes and infertility in diethylstilbestrol-exposed
infer-
the outcome
FD.
S, Secher delivery. M.
Rowland AS, Baird AJ. Reduced fertility
daughters.
Am J
after
Obstet Gynecol Stand 1988;67:115-9. G, Poulsen AO, Kirschheiner H. Changing
in pregnancy I’S, Secher biparietal study. weight.
and
J Obstet
ing, drinking, and eating behaviour among Denmark. Stand J Sot Med 1989;17:277-80.
fetal dinal fetal
delivery.
C, Killen B. Delivery outcome Fertil Steril 1991;55:726-32.
control
Epide-
with intrauterine growth J Epidemiol 1989;129:1247-57.
29
Reprod
birth.
of preterm
13. Joffe M, Li 2. Association of time to pregnancy pregnancy. Fertil Steril 1994;62:71-5. 14. de Haas I, Harlow BL, Cramer DW, Frigoletto
distress 18. Eriksen
Hum
Lester AR, Wood EC, Johnston I’D, Nial HD. pregnancy serum measured with an homoloObstet Gynecol 1987;69:585-9.
HA, Spielberger A registry study.
17. Hedegaard
following
transfer.
Study of Cervicitis and of Chlamydia trachomatis
Toth M, Witkin SS, Ledger etiology of preterm birth.
0, Anderson
pregnancies
Hopkins Association
28
1995;115:
G, Petrucco
E. Epidemiology
hominis ery. Am
1992;
T, Kolvik R, after in vitro
Lazgeforen
of singleton
GS. An epidemiologic 1981;113:81-92.
infertility. Acta 16. Olsen J, Frische
Gynecol
F, Abyholm and babies
intra-fallopian
GS, Papiernik 1993;15:414-43.
11. Berkowitz Epidemiol
Am
The Johns Outcome.
Received August 29, 1996. Received in revised form Decetnber Accepted December 30, 1996.
22, 1996.
of and
history
Copyright Gynecologists.
0
1997 by Published
Henriksen
The American by Elsevier
et al
College of Obstetricians Science Inc.
Fertility and Preterm
Delivery
and
599
and Preterm
Delivery
TINE BRlNK HENRIKSEN, MD, PhD, DONNA DAY BAIRD, PhD, J0RN OLSEN, MD, PhD, MORTEN HEDEGAARD, MD, PhD, NIELS J0RGEN SECHER, MD, AND ALLEN J. WILCOX, MD, PhD Objective:
To
higher
of preterm delivery. We used data from
risk
Methods: studies mately
test
whether
subfertile two
women
may
population-based
be
at
cohort
on risk factors and pregnancy outcome for approxi20,000 deliveries in three major Danish obstetric
departments. nant women departments
The Aalborg-Odense study comprised all pregattending routine antenatal care at two obstetric from 1984 to 1987. In all, 11,850 women (86%)
filled in a questionnaire Aarhus study addressed weeks’ gestation from was returned by 6857 with speak
chronic Danish.
at about 36 weeks’ gestation. The women at the routine visit near 16 1989 (80%).
to 1991; a study questionnaire Both studies excluded women
illnesses, multiple Only women with
fetuses, planned
and inability to pregnancies were
included in the analysis. In all, 8855 and Aalborg-Odense and Aarhus, respectively,
3985 women from were eligible for
the analyses. In according to their
both cohorts, waiting time
women were categorized to pregnancy (O-6 months,
7-12 months, and greater than 1 year) and according to examination or treatment for infertility (yes, no). Preterm delivery was defined as birth before 37 completed weeks.
Results: Compared with women who less before they conceived, women
tried for 6 months or who tried for 7-12
months had the adjusted
1.3 times (95% risk of preterm
interval in both
women with had adjusted
a time to pregnancy relative
risks
confidence delivery for
CI 1.1, 2.21 for Aalborg-Odense Aarhus. The results remained
[CI] 0.8, 2.1) cohorts, and
of greater than 12 months
preterm and similar
delivery
of 1.6 (95%
1.7 (95% CI 1.1, 2.6) for after excluding women
with infertility treatment. Conclusions: Pregnant women with subfertility and clinically defined infertility are more prone to preterm delivery, even in the absence of infertility 1997;89:594-9. 0 1997 by The
tricians
treatment. American
(Obstet College
Gynecol of Obste-
and Gynecologists.)
From the Perinntal Epidemiological Rrseurch Unit, Department @ Obstetrics and Gyrzecology, Aarhus Uniaersity Hospital, Denmark; the Danish Epidemiology Science Center, Institute cf Epidemiology and Social Medicine, Aarhus University, Denmark; and the Epidemiology Branch, National Institute qf Enz~ironmental Health Sciences, Research Triangle Park, North Carolina.
594
0029-7844/97/$17.00 PI1 SOO29-7844(97)00045-B
Assisted reproduction has been used for decades.’ Surgical procedures or hormonal treatment with or without intrauterine insemination, gamete intrafallopian transfer (GIFT), or in vitro fertilization (IVF) are used widely in couples who have difficulty getting pregnant.‘,* Women enrolled in IVF or GIFT programs have high rates (10 -20%) of preterm delivery, even with singleton pregnancies. 1*3-8 It is not clear whether these high rates of preterm delivery are due to the treatment or to some underlying problems related to infertility. An increased risk of preterm delivery has been attributed to elevated levels of relaxin after the administration of gonadotropins” and to possible intrauterine trauma or infections from the use of catheters during the procedures.” Some studies,“-I” but not a11,i4,‘” have suggested that infertility itself may be an independent risk factor for preterm birth. If women treated for infertility have a higher a priori risk of adverse pregnancy outcome, then those adverse effects may mistakenly be attributed to the treatment. We tested the hypothesis that subfertile women may be at higher risk of preterm delivery regardless of fertility treatment. Data from two Danish populationbased studies were used to evaluate the association between subfertility (measured as time to pregnancy) and preterm delivery.
Materials and Methods Two large Danish population-based studies16,17 collected data on risk factors and pregnancy outcome. Both of these projects were approved by the Regional Committees for Ethics in Science. Both studies obtained information about potential risk factors for adverse pregnancy outcome using questionnaires administered during pregnancy. Briefly, the first was part of a study that included all pregnant women in two major Danish cities (Aalborg and Odense) during a 3-year period (1984-1987). Midwives handed out the questionnaires
Obstetrics & Gynecology
at the routine antenatal visit in the 36th gestational week. More than 95% of all women with singleton pregnancies in the two regions (n = 13,815) received the questionnaire, and 11,850 (86%) responded. Some women did not attend the antenatal care program. Accordingly, they did not receive the questionnaire. Some women delivered before the antenatal visit, and in a few instances the midwife may simply have forgotten to hand out the questionnaire. Women with cardiovascular disease, epilepsy, rheumatic arthritis, diabetes, or cancer were excluded (n = 188). Of the remaining women, 303 provided no information on gestational age or time to pregnancy, leaving 11,306 women eligible for analyses. Of these, 8855 (78.3%) had planned their pregnancy. Data included maternal characteristics (age, height, pre-pregnancy weight), job history, smoking, and drinking and eating habits. Women were asked if they had ever been examined or treated for infertility, and the time between discontinuing the use of contraception and pregnancy (“pregnant in spite of contraceptive use,” O-6 months, 7-12 months, and more than 1 year). Obstetric and medical history and information about the outcome of pregnancy were collected from birth certificates and the women’s medical records. The second study was of all pregnant women attending routine antenatal care in the city of Aarhus during a 2-year period (1989-1991). The study excluded women who were unable to speak Danish, were pregnant with more than a single fetus, or were suffering a fetal death before 28 completed weeks’ gestation (n = 964). Some women delivered twice during the period; only the first pregnancy was included. In all, 8536 women were eligible for the study. At the routine antenatal visit at about 16 weeks’ gestation, women were asked to complete two questionnaires: a basic questionnaire and a primary study questionnaire. The first requested the women’s medical history, determined eligibility, ascertained the date of the last menstrual period and cycle length, and collected data on smoking and alcohol consumption. This questionnaire also obtained information on whether the pregnancy was planned and the waiting time to pregnancy in years and months. Data obtained by the second, more extensive study questionnaire included psychosocial factors, marital status, education, and occupational status. Immediately after delivery, the attending midwife made a structured report on the obstetric and medical complications during pregnancy, the course of delivery, and the condition of the newborn. These data were cross-validated by a research midwife using hospital records. The basic questionnaire was returned by 8377 (98%) of the women in the cohort, and the study questionnaire by 6857 (80%). Gestational age at delivery was calculated
VOL.
89, NO.
4, APRIL
1997
Table
1. Time to Pregnancyby Preterm Delivery: The
Aarhus Cohort Study Time to pregnancy
(mo)
AIl women (n = 3985) 56 7-12 >12 Women without infertility treatment (n = 3757) ~6 7-12 >12
n
Preterm delivery
Relative risk
2978 486 521
99 (3.3%) 21 (4.3%) 31 (6.0%)
Reference 1.3 1.8
2948 431 339
96 (3.3%) 19 (4.2%) 20 (5.9%)
Reference 1.3 1.8
from ultrasonographically determined fetal biparietal diameter, obtained before 21 completed weeks’ gestation in more than 80% of the women.” All women were offered a routine ultrasound scan; however, not all women accepted. In women without an early scan, gestational age was estimated from the last menstrual period, adjusted for the woman’s usual cycle length to a length of 28 days. Women with cardiovascular, pulmonary, or kidney diseases;diabetes or other metabolic diseases;or epilepsy diagnosed before pregnancy were excluded (n = 233). Gestational age was missing in 74 cases,leaving a study cohort of 6550women. Of these, 3985(60.8%) had planned their pregnancy. Preterm delivery was defined as delivery before 37 completed weeks. Analyses were restricted to women whose pregnancies were planned. Multiple variables were taken into account using multiple logistic regression.” Odds ratios (ORs) are presented with 95% confidence intervals (Us); statistical significance was defined as a two-sided P < .05. Potential confounding variables (categorized as shown in the tables) were tested in the multivariate analyses as dummy variables; if the variables changed the estimate of the association between time to pregnancy and preterm delivery by 10% or more, they remained in the final model.”
Results The overall rate of preterm delivery in the Aarhus study was 3.8%. This rate was the same for both planned and unplanned pregnancies. Because of the late timing of the questionnaire in the Aalborg-Odense study, the overall rate of preterm delivery was smaller (2.7%). The preterm delivery rate among planned pregnancies (2.6%) was close to that among unplanned pregnancies (3.0%). Tables 1 and 2 show the distributions of preterm deliveries by time to pregnancy. In both cohorts, the
Henriksen
et al
Fertility
and Preterm
Delivery
595
Table
2.
Time
Time to Pregnancy by Preterm Delivery: The Aalborg-Odense Cohort Study to pregnancy
(mo)
All women (n = 8855) 56 7-12 >12 Women without examination or treatment for infertility (n = 8179) ~6 7-12 >12
n
Preterm delivery
Relative risk
6529 152 (2.3%) 857 26 (3.0%) 1469 54 (3.7%)
Reference 1.3 1.6
6372 151 (2.4%) 825 23 (2.8%) 982 41 (4.2%)
Reference 1.2 1.8
rate of preterm deliveries increased with increasing time to pregnancy. Compared with women who succeeded in getting pregnant within 6 months, women with a time to pregnancy of more than 12 months had 1.6 and 1.8 times the risk of preterm delivery in the Aarhus and Aalborg-Odense studies, respectively. This pattern did not change after excluding women who had examination or treatment for infertility (Tables 1 and 2). Table 3 shows the distribution of preterm delivery by time to pregnancy, dichotomized at 1 year and stratified by potential confounding factors, for both studies. The bivariate associations shown in Tables 1 and 2 were consistent across strata: With few exceptions, the percentage of women with preterm deliveries was higher among women who took longer than 1 year to conceive. The pattern was very similar when time to pregnancy was dichotomized at 6 months (data not shown). Table 4 shows the adjusted association between time to pregnancy and preterm delivery in the two cohorts. Few of the potential confounders listed in Table 3 affected the association. Compared with women who tried for 6 months or less before they conceived, women who tried for 7-12 months had 1.3 times the risk of preterm delivery. This excess risk was not statistically significant, although it was consistent across both cohorts (Table 4). In both studies, women with a time to pregnancy of more than a year had a significantly higher risk of preterm delivery compared with women who conceived within 6 months. The adjusted ORs for preterm delivery in the two studies were 1.6 (95% CI 1.1, 2.2) and 1.7 (95% CI 1.1, 2.6), respectively. The results were not changed by excluding women with early-pregnancy bleeding, previous preterm delivery, previous spontaneous or induced abortions, examination or treatment for infertility, or induced deliveries.
Discussion Time to pregnancy of more than a year is used by clinicians to identify couples who might benefit from
596
Henriksen
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Ferti/ity and Preterm Delivery
infertility treatment. Among those who became pregnant in less than 1 year, our data allowed us to subcategorize fertility further into two groups: the more fertile who conceived in O-6 months and the less fertile who became pregnant in 7-12 months. Women with a longer time to pregnancy had an increased risk of preterm delivery in both cohorts. Women with a time to pregnancy of 7-12 months had a 30% higher risk, and women with a time to pregnancy of more than 1 year had a 60% higher risk than women who conceived within half a year of trying. Joffe and Lii3 found that pregnancies ending in a preterm delivery took 15% longer to conceive than other live births. However, the risk of preterm delivery among untreated clinically infertile women, ie, women with a time to pregnancy of more than a year, could not be derived from their study. Furthermore, the study was based on asking 33-year-old women about the outcome of past pregnancies. Even though recall of time to pregnancy and preterm delivery may be fairly accurate,‘l recall bias may be introduced by the women’s knowledge of the pregnancy outcome. We avoided this potential bias by collecting information on time to pregnancy before delivery. Most other studies on subfertility and pregnancy complications were small, with insufficient statistical power to explore the relation with preterm delivery.2~22~23 Furthermore, it has been impossible to rule out the effect of treatment because women with and without infertility treatment were not separated.‘2,‘5,22,23 Our participation rates were between 80% and 90%. Preterm delivery was slightly more common among non-responders. Thus, selection bias could occur if women with a shorter time to pregnancy were less likely to participate. However, in the Aarhus study, we found the same association between time to pregnancy and preterm delivery among women who declined to fill in the larger study questionnaire as among responders. Information on time to pregnancy among nonresponders was not available in the Aalborg-Odense study, but this study had a higher overall response rate, and selection bias due to non-response seems even less likely. It is possible that selection bias could occur by restricting the study population to women with planned pregnancies: 24 If the more fecund women who conceived despite contraceptive use had more preterm deliveries but are excluded, it will lead to an overestimation of the true association between time to pregnancy and preterm delivery. We found the same rate of preterm deliveries among planners and non-planners in the Aarhus study. Furthermore, in the Aalborg-Odense data, we had information about non-planners who became pregnant despite contraceptive use (n = 584).
Obstetrics 0 Gynecology
Table
of Preterm Delivery and Time to Pregnancy Dichotomized at 12 Months by Maternal Characteristics, Obstetric History, Life-Style, and Social Factors: The Aarhus Cohort Study (12 = 3985) and the Aalborg-Odense Cohort Study (n = SSS5)
3. Rate
_ Variable Age (y) <25 25-29 30-34 235 Pre-pregnancy ~60 60-69 270 Height (cm) Cl65 165-169 ,170 Parity 0
weight
M
VOL.
89, NO.
The Aarhus cohort -~-. ..I_TTP > 12 mo (preterm %)
The Aalborg-Odense TTP 5 12 mo (preterm 7~)
n
TTP > 12 mo (preterm 9:)
cohort
-___
TTI’ 5 12 mo (preterm 70)
534 1762 1199 490
7.8 6.0 4.3 7.9
3.7 3.9 2.8 3.3
2385 3965 1936 563
4.6 3.7 3.9 1.3
2.3 2.6 1.8 3.5
1872 1426 622
5.4 4.7 9.0
3.5 3.1 4.1
4500 2855 1183
4.6 2.3 2.3
2.6 2.2 2.3
1152 1258 1524
6.1 8.4 3.6
3.8 3.4 3.2
3156 2620 2582
4.0 2.1 3.9
2.6 2.0 2.5
2060 1442 479
5.8 6.3 6.4
4.2 2.0 4.9
4164 3633 1058
4.0 3.0 4.5
2.7 1.9 2.9
2060 1771 150
5.8 5.7 14.3
4.2 2.1 9.6
1389 1792 804
5.0 5.6 8.8
3.3 3.3 4.1
3141 4271 1443
3.9 2.8 5.7
2.7 2.2 2.5
1389 1577 1019
5.0 5.4 9.0
3.3 3.0 4.4
2229 1739
5.6 6.6
2.9 4.2
5200 3655
3.7 3.7
2.6 2.3
316 1185 2333
9.3 5.9 5.3
5.0 4.1 3.1
1300 4473 3063
3.1 3.3 4.9
2.1 2.6 2.2
2729 603 612
4.7 9.5 7.8
3.4 4.4 3.2
7202 1363 281
3.3 5.7 5.0
2.4 2.6 1.5
2711 1195
6.5 5.4
2.8 5.1
4731
3.3
2.4
1282 2803
4.9 3.8
2.4 2.5
4090 3287 1316
3.8 3.5 3.9
2.5 2.1 3.5
3025 5036 794
2.4 4.0 3.7
3.5 2.2 3.7
(kg)
22 Previous preterm delivery Primiparous 0 21 Previous spontaneous abortion Primigravida 0 21 Previous induced abortion I’rimigravida 0 21 Marital status Married Cohabitating or living alone Education (y) 7-9 10-11 212 Work status Employed Unemployed Studying Smoking Non-smoker Smoker 1-9 cigarettes/d ~10 cigarettes/d Caffeine intake (mg/d)
---
992 1373 1619
8.1 5.3 5.2
3.1 3.3 3.9
2025 1728 180
6.6 5.4 7.1
3.7 3.0 5.3
3183 802
5.4 7.5
3.1 4.8
3297 638
5.2 9.1
3.2 4.7
to pregnancy.
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Table
4.
Time to Pregnancy and Preterm Delivery: Odds Ratios and 95% Cbnfidence Intervals Adjusted for Parity and Smoking Habits by Logistic Regression Analysis, the Aarhus and the Aalborg-Odense Cohort Studies
Time to pregnancy (mo) All women 56 7-12 >12 No infertility treatment* 56 7-12 >12
The Aarhus
The AalborgOdense cohort?
cohort*
OR
957G CI
OR
95% CI
1 1.3 1.7
(n = 39851 Reference 0.8,2.1 1.1,2.6 (n = 3757)
1 1.3 1.6
(n = 8855) Reference 0.8,2.0 1.1,2.2 (n = 8179)
1 1.3 1.6
Reference 0.8,2.1 1.0,2.7
1 1.2 1.8
Reference 0.7, 1.8 1.2,2.2
OR = odds ratio; CI = confidence interval. * Adjusted for smoking and parity. + Adjusted for parity. * For the Aarhus cohort, no infertility treatment; for the AalborgOdense cohort, no examination or treatment for infertility.
These women had a decreased rate of preterm deliveries (2.2%), consistent with the general association between higher fertility and lower rates of preterm birth. Although known risk factors for preterm delivery are few,” we tested several variables as potential confounders. Only parity and smoking had a strong enough effect to be included in our final models. Furthermore, our association was not mediated by earlypregnancy bleeding, infertility treatment, or more induced deliveries among the women with a longer time to pregnancy. In the Aarhus data, there was a stronger association between time to pregnancy and preterm delivery am.ongparous women than among nulliparous women (Table 3). However, this was not corroborated by the Aalborg-Odense data. When subfertility is defined by time and not by the menstrual cycle, a long time to pregnancy may be due to long cycles. If estimation of gestational age is based on the date of the last menstrual period and cycle length is not taken into account, gestational age is overestimated and the number of preterm deliveries is underestimated in women with long cycles. This bias (which may mask a potential association between time to pregnancy and preterm delivery) has not been addressed in previous studies. However, in the Aarhus study, most gestational-age estimates were based on early ultrasound scanning, eliminating this problem. Most previous studies of pregnancy outcome among women treated for infertility compared the outcome among treated women with that of the general population. 1,6-8,‘5,25 The higher rate of twin and triplet pregnancies among women treated for infertility contributes
598
Henriksen
et al
Fertility and Preterm Delivery
some of the difference
in the rates of txeterm I
deliveries.
Thus, comparisons are often restricted to singleton births. However, the possibility has rarely been addressed that the treated population may be otherwise noncomparable with the background population. To our knowledge, no study has matched the comparison group with the treatment groups for the length of time to pregnancy, or otherwise controlled for this variable. Previous studies on singleton pregnancies primarily obtained by IVF methods revealed relative risks of 1.6-2.5 and absolute risk increases of 3.8-7.8% compared with untreated populations.‘,3,4-7 Most of these studies adjusted for differences in age and parity between treated and untreated women. However, our data suggest that the infertility history of treated women could explain much of the difference in the preterm delivery rate between women with and without infertility treatment. The association we observed between subfertility (or clinically defined infertility) and preterm delivery suggests shared causes.For instance, chlamydia infection of the female genital tract has been related to both infertility and preterm delivery.26-28 Evidence also exists that life-style factors, such as female smoking, may be related to subfertility29,30 as well as to the risk of preterm delivery,3l although smoking could not account for the association in our study. Another example is intrauterine exposure to diethylstilbestrol, which produces female infertility and preterm delivery.32,33In this case, the link may be the uterine anomalies associated with the exposure.34 Yet another mechanism could be introduced by the waiting time per se: Recent studies have shown that psychological stress’7*35 is associated with preterm delivery. Accordingly, an association between time to pregnancy and preterm delivery would appear if stressincreaseswith increasing time to pregnancy. In the Aarhus cohort, stress as measured by the General Health Questionnaire and Life Events17,35did not explain our findings (data not shown). To address the possible biologic mechanisms of our findings, further studies are needed on the association between preterm delivery and specific categories of infertility, such as infertility related to hormonal or mechanical disturbances. Furthermore, studies that identify subcategories of preterm delivery, such as preterm delivery preceded by labor or rupture of membranes, may provide valuable clues regarding a shared etiology of infertility and preterm birth.
References 1. MRC Working Party on Children Conceived tion. Births in Great Britain resulting from 1978-87. BMJ 1990;300:1229-33.
by In Vitro Fertilisaassisted conception,
Obstetrics & Gynecology
2. Hill GA, Bryan S, Herbert CM, Shah tions of pregnancy in infertile couples:
DM, Wentz AC. ComplicaRoutine treatment versus
assisted 3. Saunders
1990;75:790-4. PAL. The Australian
reproduction. DM, Mathews
Obstet Gynecol M, Lancaster
ter: Current research and future N Y Acad Sci 1988;541:7-21. 4. Doyle I’, Beral V, Maconochie weight resulting
role.
A preliminary
N.
l’reterm
and small-for-gestational-age from in-vitro fertilization.
23. Regis-
report.
Ann
low
birth-
delivery,
in livebom Hum Reprod
of infertility:
A prospective
1087-92. Bhalla AK,
Sarala
study.
G, Dhaliwal
Aust N Z J Obstet Gynaecol 24. Baird DD, Weinberg CR, associated with contraceptive
Br J Obstet
L. Pregnancy
1991;98:
following
infertility.
1992;3:249-51. Schwingl P, Wilcox AJ. Selection practice in time-to-pregnancy
ies. Ann N Y Acad Sci 1994;709:156-64. 25. Ezra Y, Schenker JG. Appraisal of in vitro Gynecol Reprod Biol 1993;48:127-33.
singleton babies 1992;7:425-8.
Gynaecol
fertilization.
bias stud-
Eur J Obstet
5. Olivennes F, Rufat P, Andre B, Pourade A, Quiros MC, Frydman R. The increased risk of complication observed in singleton pregnancies resulting from in-vitro fertilization (IVF) does not seem to be
26. Czerwenka K, Heuss F, Hosmann J, Manavi M, Jelincic D, Kubista E. Salpingitis caused by Chlamydia trachomatis and its sign& cance for infertility. Acta Obstet Gynecol Stand 1994;73:711-5.
related to the IVF method itself. Hum Reprod 1993;8:1297-300. 6. Tan SL, Doyle I’, Campbell S, Beral V, Rizk B, Brinsden P, et al. Obstetric outcome of in vitro fertilization pregnancies compared
27.
with
normally
conceived
pregnancies.
167:778-4. 7. van Diiring V, Maltau JM, Ertzeid G, et al. Pregnancies,
Forsdahl births
fertilization in Norway, 1988-91. 2054-60. 8. Wang JX, Clark AM, Kirby CA, G, et al. The obstetric
outcome
in-vitro fertilization/gamete 1994;9:141-6. 9. Bell RJ, Eddie LW, Relaxin in human gous radioimmunoassay. 10. Berkowitz miol Rev
12. Ghazi tility:
J Obstet
Tidsskr
Nor
Philipson
of preterm
study
preterm birth: A case 165:1290-6. 15. Varma TR, Pantel RH,
study.
Bhathenia
Am
RK.
Outcome
M, Henriksen
TB, Sabroe
and preterm NJ, Weis-Bentzon
Gynecol
1991;
of pregnancy
after
women
S. Applied logistic regression. New York: 1989. and variable selection in epidemiologic
22.
time-to-pregnancy. Li TC, MacLeod
Fertil Steril 1993;60:99-104. I, Singhal V, Duncan SLB.
The
neonatal
of pregnancy
a previous
VOL.
89, NO.
4, APRIL
1997
in women
M. Long-term
with
obstetric
recall
preterm
deliv-
W, Thaler H. The role of infection Obstet Gynecol 1988;71:723-6.
31
consumption and infertility. Int J Epidemiol 1983;12:179-84. Wisborg K, Henriksen TB, Hedegaard M, Secher NJ. Smoking
P, Schindt
AV,
oxide.
DL, Shy CM, Wilcox as dental assistants
30
32
of nitrous
in the
Damsbo
preterm delivery. Br J Obstet Gynaecol Herbst AL, Hubby MM, Blough RR, pregnancy experience in DES-exposed Herbst among
J Reprod
Med
N Engl
N. Tobacco
Frey
alcohol and
1996;103:800-5. Azizi F. A comparison and DES-unexposed
NJ, Hatch
life events affect duration of gestation Epidemiology 1996;7:339-45.
requests
use,
of
K. Abortion and pregnancy loss women. Semin Reprod Endocri-
Am J Obstet Gynecol 1986;154:1312-8. Hedegaard M, Henriksen TB, Secher
reprint
1992;327:
1980;24:62-9.
AL, Senekjian EK, diethylstilbestrol-exposed
stressful delivery?
J Med
M. Upper
MC, and
Sabroe risk
genital women. S. Do
of preterm
to:
Tine Brink Henriksen, MD, PhD Perinatal Epidemiological Research Unit Department of Obstetrics and Gynecology Aarhus University Hospital Skejby Aarhus N, DK-8200
Denmark
in a longituin predicting
21.
outcome
in
1993;307:234-9. growth of the
analysis. Am J Public Health 1989;79:340-9. Joffe M, Villard L, Li Z, Plowman R, Vessey
and
Pregnancy Mycoplasma
exposed to high 993-7. Olsen J, Rachootin
Address
smok-
NJ. Psychological
BMJ Normal
diameter and the abdominal diameter An evaluation of the two parameters Acta Obstet Gynecol Stand 1985;64:65-70.
19. Hosmer DW, Lemeshow John Wiley and Sons, 20. Greenland S. Modeling
of
Spontaneous
pregnant
retardation
DD, Weinberg CR, Shore among women employed levels
Adverse and
no1 1989;7:124-9. Kaufman RH, Adam E, Noller K, Irwin JF, Gray tract changes and infertility in diethylstilbestrol-exposed
infer-
the outcome
FD.
S, Secher delivery. M.
Rowland AS, Baird AJ. Reduced fertility
daughters.
Am J
after
Obstet Gynecol Stand 1988;67:115-9. G, Poulsen AO, Kirschheiner H. Changing
in pregnancy I’S, Secher biparietal study. weight.
and
J Obstet
ing, drinking, and eating behaviour among Denmark. Stand J Sot Med 1989;17:277-80.
fetal dinal fetal
delivery.
C, Killen B. Delivery outcome Fertil Steril 1991;55:726-32.
control
Epide-
with intrauterine growth J Epidemiol 1989;129:1247-57.
29
Reprod
birth.
of preterm
13. Joffe M, Li 2. Association of time to pregnancy pregnancy. Fertil Steril 1994;62:71-5. 14. de Haas I, Harlow BL, Cramer DW, Frigoletto
distress 18. Eriksen
Hum
Lester AR, Wood EC, Johnston I’D, Nial HD. pregnancy serum measured with an homoloObstet Gynecol 1987;69:585-9.
HA, Spielberger A registry study.
17. Hedegaard
following
transfer.
Study of Cervicitis and of Chlamydia trachomatis
Toth M, Witkin SS, Ledger etiology of preterm birth.
0, Anderson
pregnancies
Hopkins Association
28
1995;115:
G, Petrucco
E. Epidemiology
hominis ery. Am
1992;
T, Kolvik R, after in vitro
Lazgeforen
of singleton
GS. An epidemiologic 1981;113:81-92.
infertility. Acta 16. Olsen J, Frische
Gynecol
F, Abyholm and babies
intra-fallopian
GS, Papiernik 1993;15:414-43.
11. Berkowitz Epidemiol
Am
The Johns Outcome.
Received August 29, 1996. Received in revised form Decetnber Accepted December 30, 1996.
22, 1996.
of and
history
Copyright Gynecologists.
0
1997 by Published
Henriksen
The American by Elsevier
et al
College of Obstetricians Science Inc.
Fertility and Preterm
Delivery
and
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